Post Transcriptional Control of hemorrhagic iron damage.

描述（由申请人提供）：出血性中风后，随后的红细胞溶解释放出毒性水平的血红素，然后在大脑中释放出危险的过量游离铁。血液结合素（HPX）不仅与血液中过量的血红素结合，而且可以发出遗传反应的信号以适应性地调节脑中的细胞内铁稳态途径以适应出血性应激。 我们正在评估HPX如何控制铁调节蛋白（IRP 1和IRP 2）依赖的铁蛋白（Ftn，用于安全铁储存）和转铁蛋白受体（TfR，用于铁摄取）的转录后表达，以优化铁稳态途径，更好地保护脑神经元。重要的是，我们将确定HPX如何修改IRP调节网络，以适应性地控制膜铁转运蛋白（用于铁输出）及其受体的神经元翻译。 结合伴侣，淀粉样前体蛋白（APP）。我们的实验室表明，APP（s）提供了显着的和新的保护性铁氧化酶的行动，也有利于ferroportin依赖流出多余的铁从脆弱的神经元。在铁流入时，IRP 1和IRP 2从IRE解离，从而从翻译块释放Ftn和APP，以安全储存铁。因此，我们的目标是确定hemopexin如何有利地重置这种IRE介导的IRP 1/IRP 2控制APP和铁蛋白基因表达，从而促进安全的神经元铁输出和储存。 铁蛋白和APP都赋予细胞保护作用，因为活性铁氧化酶将Fe 2+转化为Fe 3+的储存形式。为了启动该反应，过量的铁结合分泌的APP中的REXXE结构域，然后氧化并将其安全地运输/储存在铁蛋白中。在这里，我们将测试ths通路是否足以保护神经元免受血红素加重的损伤。本研究拟建立胶原酶注射致出血的实验模型。然后将有可能解决血红素结合蛋白如何通过调节APP中的REXXE结构域的活性并经由APP和铁蛋白mRNA的5 '非翻译区中的铁响应元件（IRE）茎环来诱导这些针对来自血红素的过量铁的神经保护性应答。'

DESCRIPTION (provided by applicant): After hemorrhagic stroke, subsequent lysis of red blood cells releases toxic levels of heme and then a dangerous excess of free iron in the brain. Hemopexin (HPX) not only binds to excess heme in the blood, but may signal a genetic response to adaptively modulate intracellular iron homeostatic pathways in the brain to adapt to hemorrhagic stresses. We are assessing how HPX controls Iron-regulatory Protein (IRP1 and IRP2) dependent post-transcriptional expression of ferritin (Ftn, for safe iron storage), and transferrin receptor (TfR for iron uptake) in order to optimize iron homeostasis pathways to better protect brain neurons. Critically, we will determine how HPX modifies the IRP regulatory network to adaptively control neuronal translation of ferroportin (for iron export) and that of its binding partner, the amyloid precursor protein (APP). Our lab showed that APP(s) provides significant and novel protective ferroxidase action that also facilitates ferroportin dependent efflux of excess iron from vulnerable neurons. Upon iron influx, IRP1 and IRP2 dissociate from IREs thus releasing Ftn and APP from a translational block for safe storage of iron. Thus our goal is to determine how hemopexin favorably resets this IRE-mediated IRP1/IRP2 control of APP and ferritin gene expression and thereby promotes safe neuronal iron export and storage. Both ferritin and APP confer cytoprotection as active ferroxidases converting Fe2+ to its storage form of Fe3+. To start this reaction excess iron binds REXXE domain in secreted APP(s) and then oxidizes and safely transports/stores it in ferritin. Here, we will test the sufficiency of ths pathway to protect neurons against heme-aggravated damage. We will set up the experimental model of collagenase injection to experimentally induce hemorrhage. It will then be possible to address how hemopexin induces these neuroprotective responses against excess iron from heme by modulating the activity of the REXXE domain in APP and via the iron- responsive elements (IRE) stem loops in the 5'untranslated regions of APP and ferritin mRNAs. '